PROJECT SUMMARY The proposed career award is designed support the PI?s advanced training in cancer survivorship research and neuroimaging, while examining how changes in estrogen function with endocrine therapy (ET) influence brain health in breast cancer survivors. Both broad goals are consistent with the NCI?s mission to support research related to the continuing care of cancer patients and survivorship. ET is widely used to treat hormone receptor positive breast cancer and prevent recurrence by downregulating estrogen function. However, ETs readily cross the blood brain barrier and interfere with the action of estrogen in the brain. Estrogen supports cognition and menopausal status is closely linked to cognitive health in women. This has raised concern that anti-estrogen ETs may affect cognition and brain health. However, evidence across existing studies is inconsistent and these effects remain poorly understood. The incomplete understanding of the effects of ET are likely due to limitations of earlier studies ? namely, the under-appreciation of the role of menopausal status and insensitivity of standard cognitive measures. To address these limitations, the proposed study will probe the effects of ET on brain health from a women?s health perspective by examining the interaction between ET and menopausal status using sensitive functional magnetic resonance imaging (fMRI) measures of task-related brain activity. We aim to conduct a cross-sectional study in a 2x2 factorial design comparing menopausal status (pre and post) and patient group (breast cancer survivors on ET and healthy controls matched on age, race, education, and time since final menstrual period (post only)). We will use sensitive fMRI measures of brain activity during a working memory task ? measures successfully used to reveal the effects of menopause and estrogen changes in healthy women, but yet to be extensively used to study the effects of ET. We hypothesize that task-related hyperactivity in pre-frontal regions will be observed in breast cancer survivors on ET compared to controls. Further, ET may more dramatically disrupt estrogen function in pre-menopausal women. We therefore hypothesize that the magnitude of ET effects will be greater in pre-menopausal women. We will also examine and compare the effects of ET on standard cognitive measures and novel cellular aging measures. In addition, lifetime hormone exposure histories will be explored as possible moderating factors ? the first such interrogation of these important factors. In carrying out this study, the PI, a clinical neuropsychologist in this field, will train in fMRI and cellular aging methods, while refining executive skills in clinical research in breast cancer survivorship. These acquired skills are highly relevant to the PI?s career goal of launching a vigorous research program on brain health in cancer survivorship, women?s health, and aging ? a critical intersection for healthcare needs in the U.S.